AMPK-FOXO1信号通路调节Ⅰ型子宫内膜癌细胞增殖的分子机制

Metabolic disorder and excess unopposed hormone play a crucial role in type Ⅰ endometrial cancer. Our previous studies indicated that metformin inhibited type Ⅰ endometrial cancer cell growth by activating the AMPK–FOXO1 pathway, but the relationship between AMPK-FOXO1 pathway and progestin resistance is still unclear. Our hypothesis is that metformin may increase PR expression and reduce progestin resistance by activating AMPK-FOXO1 signal pathway. The proposal is designed: (1) To investigate the expression level of pAMPK, FOXO1 and PR in the biopsy samples of type Ⅰ endometrial cancer and their correlation with clinicopathologic features. (2) To investigate the role and molecular mechanism of AMPK- FOXO1 pathway in progestin resistance with both in vitro experiment and vivo experiments. We expect that this project will provide scientific clues for future clinical trials for type Ⅰ endometrial cancer treatment.

Ⅰ型子宫内膜癌是与机体能量代谢紊乱及激素长期作用密切相关的常见妇科恶性肿瘤。我们前期研究证明二甲双胍通过激活AMPK，促进FOXO1表达抑制Ⅰ型子宫内膜癌细胞增殖并诱导细胞凋亡，但AMPK-FOXO1信号通路与孕激素耐药的关系尚不清楚。AMPK-FOXO1信号通路是调控细胞能量代谢、生长分化的重要信号通路，二甲双胍是否通过激活AMPK-FOXO1信号通路诱导PR表达、增强孕激素的作用，值得探索。本项目拟通过研究：①明确Ⅰ型子宫内癌病理组织中pAMPK、FOXO1及PR表达水平与临床病理的关系；②应用siRNA、信号通路抑制等方法，通过系列体内外实验，深入探讨二甲双胍与孕激素耐药的关系，同时明确AMPK-FOXO1通路在二甲双胍抑癌机制中的作用和调控机制，从而为Ⅰ型子宫内膜癌防治和孕激素耐药研究提供新的理论依据。

Ⅰ型子宫内膜癌是与机体能量代谢紊乱及激素长期作用密切相关的常见妇科恶性肿瘤。我们前期研究证明二甲双胍通过激活AMPK，促进FOXO1表达抑制Ⅰ型子宫内膜癌细胞增殖并诱导细胞凋亡，但AMPK-FOXO1信号通路与孕激素耐药的关系尚不清楚。AMPK-FOXO1信号通路是调控细胞能量代谢、生长分化的重要信号通路，二甲双胍是否通过激活AMPK-FOXO1信号通路诱导PR表达、增强孕激素的作用，值得探索。本项目拟进一步通过通过系列体内外实验：①明确Ⅰ型子宫内癌病理组织中pAMPK、FOXO1及PR表达水平与临床病理的关系；②应用siRNA、信号通路抑制等方法，深入探讨二甲双胍与孕激素耐药的关系，同时明确AMPK-FOXO1通路在二甲双胍抑癌机制中的作用和调控机制，从而为Ⅰ型子宫内膜癌防治和孕激素耐药研究提供新的理论依据。